Cellular Strategies for Tolerance Induction

耐受诱导的细胞策略

• 批准号: 10609610
• 负责人: CHRISTIAN P LARSEN
• 金额: $ 69.45万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10609610
• 关键词: Address; Adoptive Transfer; Allografting; Antibody Therapy; Antigens; Autoimmunity; Biological Models; Bone Marrow; Cell Therapy; Chimerism; Chronic; Clinic; Clinical; Clinical Trials; Complex; Data; Development; Education; End stage renal failure; Ensure; Exposure to; Face; Goals; Health; Hematopoiesis; Hematopoietic; Immune; Immune Tolerance; Immunity; Immunosuppression; Immunosuppressive Agents; Kidney Transplantation; Lead; Life; Longevity; Macaca mulatta; Mediating; Modeling; Morbidity - disease rate; Mus; Organ Transplantation; Pathway interactions; Patient Care; Patients; Pattern; Pharmacology; Pre-Clinical Model; Preparation; Prevention; Publishing; Regimen; Regulatory T-Lymphocyte; Risk; Solid; System; T-Lymphocyte; Testing; Thymus Gland; Toxic effect; Translations; Transplant Recipients; Transplantation; Transplantation Tolerance; allograft rejection; base; central tolerance; clinical application; clinically relevant; combinatorial; design; experience; experimental study; graft vs host disease; immunomodulatory strategy; immunoregulation; improved; in vivo; isoimmunity; kidney allograft; mortality; mouse model; nonhuman primate; novel; preservation; response; success; trafficking; translational approach; translational model

Renal transplantation represents first-line therapy for patients with ESRD, with the most recent data documenting significant one-year success rates. However, patients continue to face high morbidity and mortality after transplant, both from chronic allograft rejection and from the toxicities associated with standard immunosuppressive regimens. Given these dual risks, the ultimate goal in this field is the induction of immune tolerance after transplantation, which promises life-long acceptance of an allograft, without the need for ongoing immunosuppression and importantly, with preservation of protective immunity. While novel pharmacologic and antibody-based therapies represent real promise in terms of greatly prolonging allograft survival and reducing off-target toxicities, murine studies strongly suggest that the most robust strategies for inducing immune tolerance incorporate cellular therapies, including both mixedchimerism induction (especially in combination with T cell costimulation blockade) and regulatory T cell (Treg)-based approaches. Both of these therapies hold the promise of fundamentally resetting recipient immunity in favor of allograft acceptance, and thus provide a direct pathway towards immune toleranceinduction. In this Project, we will explore the following Aims, each designed to advance the use of cellular therapies for tolerance induction after renal transplantation: Specific Aim #1: To induce immune tolerance to a renal allograft through the induction of stable, full-spectrum mixed-hematopoietic chimerism in the setting of T cell costimulation blockade. Specific Aim #2: To utilize regulatory T cells to induce stable, full-spectrum mixed-chimerism and immune tolerance during renal transplantation.

根据最新数据，肾移植是 ESRD 患者的一线治疗方法 记录显着的一年成功率。然而，患者仍然面临着高发病率和 移植后的死亡率，包括慢性同种异体移植排斥和与移植物相关的毒性 标准免疫抑制方案。考虑到这些双重风险，该领域的最终目标是 移植后诱导免疫耐受，这保证了同种异体移植物的终生接受， 不需要持续的免疫抑制，重要的是，可以保留保护性免疫力。 虽然基于药物和抗体的新型疗法在很大程度上代表了真正的希望 小鼠研究强烈表明，延长同种异体移植物的存活率并减少脱靶毒性 诱导免疫耐受的稳健策略结合了细胞疗法，包括混合嵌合诱导（特别是与 T 细胞共刺激阻断相结合）和调节性 T 细胞 基于 Treg 的方法。这两种疗法都有望从根本上重置接受者 免疫有利于同种异体移植物的接受，从而提供了诱导免疫耐受的直接途径。在这个项目中，我们将探索以下目标，每个目标都旨在促进蜂窝技术的使用 肾移植后耐受诱导疗法：具体目标#1：诱导免疫耐受 通过在肾中诱导稳定的全谱混合造血嵌合体来形成肾同种异体移植物 T 细胞共刺激阻断的设置。 具体目标#2：利用调节性 T 细胞诱导稳定、全谱混合嵌合和免疫 肾移植期间的耐受性。